This proposal will provide the applicant, John Scott, with training in the design and conduct of clinical trials and kinetics studies. Dr. Scott completed training in Infectious Diseases and will complete a Masters degree in Epidemiology. During his fellowship, he studied virologic aspects of hepatitis C infection in Native Alaskans and determinants of viral persistence. This project describes his research interests in viral kinetics in serum and extrahepatic compartments and determinants of viral relapse. Treatment of HCV with peginterferon and ribavirin has improved response rates markedly;however, it is still quite low in certain populations and the treatment is expensive and toxic. A major reason for the suboptimal response is relapse upon stopping therapy. The reason for relapse is unknown, but extrahepatic sites may contribute. We will use kinetics models to better define the mechanism of relapse and improve on current models so that duration of therapy can be optimized. Specific Aim 1: To define the replication kinetics between persons with high sustained virologic response (SVR) rates and high likelihood of response to peginterferon/ribavirin therapy and those with low SVR and high relapse rates with peginterfron/ribavirin therapy. We hypothesize that patients who are relatively resistant to peginterferon and ribavirin either due to a known predictor of treatment failure or as yet unidentified host or virologic characteristics will exhibit as lower decline in HCV RNA in plasma during the induction (first phase) or second phase of viral inhibition. Specific Aim 2: To define the association between persistent HCV in hepatic and extrahepatic sites and sustained virologic response or relapse from antiviral therapy. We hypothesize that lower SVR and higher relapse rates will be associated with 1) detection of HCV RNA in both hepatic and extrahepatic reservoirs;and 2) slower decline of HCV RNA in extrahepatic compartments between those who relapse after completion of therapy and those who do not.